Essential role of O-GlcNAcylation on the survival and function of serotonergic neurons

Abstract

O-GlcNAcylation is a post-translational modification that attaches O-linked β-N-acetylglucosamine (O-GlcNAc) to serine/threonine residue of proteins. O-GlcNAcylation plays an essential role in key cellular processes such as transcription, translation, and protein homeostasis. Notably, O-GlcNAcylation and two related enzymes, O-GlcNAc transferase (OGT) and O-Glc- NAcase (OGA), are highly enriched in the brain and numerous neuronal proteins are known to be O-GlcNAcylated, while our understanding of the functional role of O-GlcNAcylation remains rudimentary in the brain. Serotonergic neurons in the raphe nuclei project their axon fibers relatively evenly to almost all brain regions and are essential for diverse brain functions. Despite this functional significance, however, there still remains a good deal of uncertainty as to how serotonergic neurons and their activities are regulated at the molecular level. In this study, we investigated the role of post-translational modification O-GlcNAcylation in raphe serotonergic neurons. We found that down-regulation of O-GlcNAcylation in serotonergic neurons causes a marked effect on cell survival. In addition, genetic up-regulation of O-GlcNAcylation led to the changes in synaptic functions of serotonergic neurons and serotonin-related behaviors. Given the recent findings of molecular and cellular heterogeneity of raphe serotonergic neurons, our findings will provide new insights into the molecular mechanisms by which serotonergic neurons and serotonin-related behaviors are controlled in the brain.